title: The inclusion complex of 4-hydroxynonenal with a polymeric derivative of β-cyclodextrin enhances the antitumoral efficacy of the aldehyde in several tumor cell lines and in a three-dimensional human melanoma model.
abstract: 4-Hydroxynonenal (HNE) is the most studied end product of the lipoperoxidation process, by virtue of its relevant biological activity. The antiproliferative and proapoptotic effects of HNE have been widely demonstrated in a great variety of tumor cell types in vitro. Thus, it might represent a promising new molecule in anticancer therapy strategies. However, the extreme reactivity of this aldehyde, as well as its insolubility in water, a limiting factor for drug bioavailability, and its rapid degradation by specific enzymes represent major obstacles to its possible in vivo application. Various strategies can used to overcome these problems. One of the most attractive strategies is the use of nanovehicles, because loading drugs into nanosized structures enhances their stability and solubility, thus improving their bioavailability and their antitumoral effectiveness. Several natural or synthetic polymers have been used to synthesize nanosized structures and, among them, β-cyclodextrin (βCD) polymers are playing a very important role in drug formulation by virtue of the ability of βCD to form inclusion compounds with a wide range of solid and liquid molecules by molecular complexation. Moreover, several βCD derivatives have been designed to improve their physicochemical properties and inclusion capacities. Here we report that the inclusion complex of HNE with a derivative of βCD, the βCD-poly(4-acryloylmorpholine) conjugate (PACM-βCD), enhances the aldehyde stability. Moreover, the inclusion of HNE in PACM-βCD potentiates its antitumor effects in several tumor cell lines and in a more complex system, such as a human reconstructed skin carrying melanoma tumor cells.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy. Electronic address: stefania.pizzimenti@unito.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pizzimenti
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Eric
authors.initials: E
authors.lastname: Ciamporcero
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Pettazzoni
authors.affiliation: Section of Dermatology, Department of Medical Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Osella-Abate
authors.affiliation: Section of Dermatology, Department of Medical Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Novelli
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Toaldo
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Husse
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Daga
authors.affiliation: Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Minelli
authors.affiliation: Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Bisazza
authors.affiliation: Department of Chemistry, University of Milan, Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferruti
authors.affiliation: Department of Chemistry, University of Milan, Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ranucci
authors.affiliation: Section of Dermatology, Department of Medical Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia Bernengo
authors.affiliation: Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dianzani
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Biasi
authors.affiliation: Section of Dermatology, Department of Medical Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cavalli
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Barrera
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy*; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D000447:Aldehydes; D000970:Antineoplastic Agents; D004337:Drug Carriers; D047392:beta-Cyclodextrins; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxynonenal; Free radicals; Nanotechnology; Three-dimensional human melanoma model; Tumor cell lines; β-Cyclodextrin–poly(4-acryloylmorpholine) conjugate